Styrene maleic acid-pirarubicin disrupts tumor microcirculation and enhances the permeability of colorectal liver metastases.
BACKGROUND
Doxorubicin is a commonly used chemotherapy limited by cardiotoxicity. Pirarubicin, derived from doxorubicin, selectively targets tumors when encapsulated in styrene maleic acid (SMA), forming the macromolecular SMA pirarubicin. Selective targeting is achieved because of the enhanced permeability and retention (EPR) effect. SMA-pirarubicin inhibits the growth of colorectal liver metastases, but tumor destruction is incomplete. The role played by the tumor microcirculation is uncertain. This study investigates the pattern of microcirculatory changes following SMA-pirarubicin treatment.


METHODS
Liver metastases were induced in CBA mice using a murine-derived colon cancer line. SMA-pirarubicin (100 mg/kg total dose) was administered intravenously in 3 separate doses. Twenty-four hours after chemotherapy, the tumor microvasculature was examined using CD34 immunohistochemistry and scanning electron microscopy. Tumor perfusion and permeability were assessed using confocal in vivo microscopy and the Evans blue method.


RESULTS
SMA-pirarubicin reduced the microvascular index by 40%. Vascular occlusion and necrosis were extensive following treatment. Viable cells were arranged around tumor vessels. Tumor permeability was also increased.


CONCLUSIONS
SMA-pirarubicin damages tumor cells and the tumor microvasculature and enhances tumor vessel permeability. However, tumor necrosis is incomplete, and the growth of residual cells is sustained by a microvascular network. Combined therapy with a vascular targeting agent may affect residual cells, allowing more extensive destruction of tumors.
Daruwalla
Jurstine
J
Department of Surgery, University of Melbourne, Austin Hospital, Studley Road, Heidelberg, Victoria 3084, Australia. jurstine@pgrad.unimelb.edu.au
Greish
Khaled
K
Malcontenti-Wilson
Cathy
C
Muralidharan
Vijayaragavan
V
Iyer
Arun
A
Maeda
Hiroshi
H
Christophi
Chris
C
D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016503:Drug Delivery Systems; D007150:Immunohistochemistry; D008114:Liver Neoplasms, Experimental / Q000556:secondary*; D008297:Male; D008298:Maleates / Q000008:administration & dosage*; D051379:Mice; D008808:Mice, Inbred CBA; D008833:Microcirculation / Q000187:drug effects; D018613:Microscopy, Confocal; D009336:Necrosis; D010539:Permeability; D020058:Styrene / Q000008:administration & dosage*
D018952:Antigens, CD34; D000970:Antineoplastic Agents; D008298:Maleates; D020058:Styrene; D004317:Doxorubicin; C030272:maleic acid; C027260:pirarubicin